Protein prenyltransferases, such as protein farnesyltransferase (FTase), RabGGTase (or GGTase-II) and protein geranylgeranyltransferase type I (GGTase-I), catalyze posttranslational modification of proteins, often involving the addition of isoprenoids. For example, protein geranylgeranylation catalyzes the transfer of a C20 geranylgeranyl group from geranylgeranyl pyrophosphate to proteins ending with the CAAL motif (C is cysteine, A is an aliphatic amino acid and L is leucine or phenylalanine). Geranylgeranylated proteins include, for example, RhoA, RhoC, Rap1, Ral, Rac, Cdc42, as well as gamma-subunit of heterotrimeric G-proteins.
Certain protein prenyltransferases, including GGTase I, RabGGTase and FTase, have been implicated in cancer processes. See Carrico et al. (2005) Bioorg. Med. Chem. 13, 677-688 and Peterson et al. (2006) J Biol Chem. 286, 25935-25946. Studies have also demonstrated the physiological significance of prenyltransferases, including protein geranylgeranylation, in cancer. Knockout mice specific for the beta-subunit of GGTase-I have been established, and the GGTase-I deficiency was shown to result in reduced K-ras-induced lung tumor formation and dramatically increased survival (Sjogren et al. (2007) J. Clin. Invest. 117, 1294-1304). Characterization of GGTase-I-deficient cells showed proliferation inhibition and accumulation of p21CIP1/WAF1, pointing to the significance of GGTase-I in cell proliferation and cell cycle progression. GGTase-I deficiency reduced oncogenic K-ras-induced lung tumor formation in mice, pointing to the significance of inhibiting GGTase-I to block tumor formation. Recent studies also showed that a number of geranylgeranylated proteins play important roles in tumorigenesis and metastasis. In addition to RhoA and Cdc42 proteins (Lim et al. (2005) Cancer Cell 6, 533-545), RalA protein was recently found to be activated downstream of Ras in most pancreatic cancer cells harboring an oncogenic K-ras mutation. RalB plays critical roles in the survival pathway (Chien et al. (2003) EMBO Rep. 4, 800-806). RhoC is overexpressed in metastatic cancer and RhoC knockout mice exhibit defect in metastasis (Clark et al. (2000) Nature 406, 532-535; Hakem et al. (2005) Genes and Develop. 19, 1974-1979). Overexpression of Rab25 in breast and ovarian cancer cells has been reported, and this mutation is a determinant for aggressiveness of these cancers (Cheng et al. (2004) Nat. Med. 10, 1251-1256; Cheng et al. (2005) Cancer Res. 65, 2516-2519). Rab25 is also upregulated in prostate cancer and transitional-cell bladder cancer (Cheng et al. (2004), supra). Overexpression of other Rab proteins such as Rab5a and Rab7 in cancer has been reported (Croizet-Berger et al. (2002) Proc. Nat. Acad. Sci. USA 99, 8277-8282; He et al. (2002) Gene Expr. 10, 231-242).
Several geranylgeranyltransferase type I inhibitors (GGTIs) have been identified. Most of these are derived from the CAAL peptide. See, e.g, (a) Farnesyltransferase inhibitors in cancer therapy (eds. Sebti, S. M. and Hamilton, A. D.) Humana Press, (b) Oualid et al. (2005) J. Comb. Chem. 7, 703-713, (c) Carrico et at (2005) (supra), and (d) Peterson et al. (2006) (supra).
Studies in a parent of the present patent application, PCT/US2008/009106, incorporated by reference herein in its entirety, describe analyzing libraries of small molecules generated by combinatorial chemistry, constructed by phosphine catalysis of allenoate compounds, and identify a variety of small molecule chemical compounds which specifically inhibit GGTase I and/or RabGGTase, in some cases by competing with a substrate protein. The GGTI compounds block the protein modification and inhibit membrane association and function of, e.g., Ral, Rho and Rap subfamilies. The GGTI compounds were shown to inhibit the proliferation of a variety of human cancer cells, to cause G1 cell cycle arrest and induction of p21CIP1/WAF1, and to exhibit antitumor activity in mouse models.
There exists a need to develop efficient drug delivery systems that preferentially deliver to cancer cells and tumors molecules such as the GGTI and RabGGTase inhibiting compounds described by the present inventors.